Specific Aims. There are six major goals to be pursued during the next grant period; much of the proposed chemistry depends on the chemistry of 2,5-cyclohexadienones: 1) The intramolecular cycle-addition of biradicals generated from photolysis of spiro[2.5]octa-1,4-dien-3-ones will be developed. This new cascade process is expected to provide synthetic organic chemists with a powerful strategy for the construction of complex carbocyclic and heterocyclic ring systems. The key to the proposed study is the development of a general method of synthesis of spiro[2.5]octa-1,4- dien-3-ones from benzoic acid derivatives. 2) The exploration and development of fragmentation reactions of chiral 1-oxo-3-iodocyclohexane- 2,4-carbolactones is expected to provide efficient synthetic routes to 3,5-disubstituted and 3,5,5-trisubstituted butenolides, 2-alkyl-4 hydroxycyclohexenones, and 5-substituted butyrolactones all as single enantiomers. An asymmetric total synthesis of the stemona alkaloid (-)- stemoamide will demonstrate an important synthetic linkage between aromatic carboxylic derivatives and natural products containing a highly substituted butyrolactone ring system. 3) It is expected that an efficient asymmetric synthesis of (-)-vindoline component of the important carcinostatic drugs vinblastine and vincristine will be completed during the next grant period. The strategy begins with the asymmetric Birch reduction alkylation of a chiral 5-aryl-2 methoxybenzamide and involves the completely regio- and stereoselective intramolecular cycloaddition of an azide to a 2,5-cyclohexadien-1-one to give an aziridine. 4) Syntheses of the potent anti-ulcerogenic agent cassiol in racemic and single enantiomer modifications will be completed. Mechanistic information concerning the diastereoselectivities of alkylations of enolates generated from Birch reduction of 3-benzopyranones is the long-term goal of this study. 5) An asymmetric synthesis of zoanthamide a complex zoanthamine- type alkaloid with seven contiguous stereogenic centers in the tetracyclic core structure will be carried out during the next grant period. We expect to complete asymmetric total syntheses of (+)-lycopodine by way of a variant of the hypothetical tandem radical cyclization-hydrogen transfer and the melodinus alkaloid (+)-meloscine by modification of the strategy already developed for asymmetric synthesis of the core tricyclic structure.